Recent developments of research have proven that cancer is a genetic disease in which multiple genetic mutations accumulate in somatic cells, resulting in uncontrolled cell growth. p53 is the tumor suppressor gene in which abnormalities have been found most frequently in human cancers, and has been clarified to have a variety of physiological functions including induction of G1 arrest and apoptosis, and checkpoint control when DNA is damaged. It is thought that these functions are exercised when p53 acts as a transcription factor to control the expression of the target gene. It is suggested that p53 abnormalities are associated with cancer malignancy, resistance to anti-cancer agents and radiation therapy, metastasis and vascularization (The New England Journal of Medicine Vol. 329 p. 1318 (1993), etc.).
Ribonucleotide reductase is a rate-limiting enzyme, which converts ribonucleotides to their corresponding deoxyribonucleotides and supplies them for purposes of DNA synthesis (Science Vol. 260 p. 1773 (1993)). This enzyme is a heterodimer comprising a large subunit (R1) and a small subunit (R2), with both R1 and R2 (National Center for Biotechnology Information GenBank Accession No. X59618) consisting of homodimers. Enzyme activity is controlled by the amount of R2. The amount of R2 is controlled depending on the cell cycle, with the most being highly expressed during the S period. Ribonucleotide reductase has been well studied in yeasts, and three subunits (RNR1, RNR2, RNR3) are known to exist in yeasts. RNR1 and RNR3 correspond to R1 in mammals and RNR2 to R2 in mammals, and control of RNR1 expression is dependent on cell cycle. It has been reported that when DNA is damaged by irradiation for example, RNR1 expression is not induced, but induction of RNR3 expression increases more than 100 fold (Genes & Development Vol. 4 p. 740 (1990)). It has also been reported that expression of R2 is greater in highly malignant cancer cells, which are resistant to anti-cancer agents and radiation therapy (Biochemistry and Cell Biology Vol. 68 p. 1364 (1990)).
The TP53R2H gene obtained in the examples below has a ribonucleotide reductase signature sequence, which has high homology with R2 and is conserved among species, and the product of the TP53R2H gene may be involved in supplying deoxyribonucleotide for DNA synthesis. Since expression of TP53R2H is also induced by DNA damage due to anti-cancer agent treatment or irradiation (not the case with R2), it may be involved particularly in supplying deoxyribonucleotides during DNA repair following DNA damage. It can therefore be expected that blocking of TP53R2H in cases of highly malignant cancer with resistance to anti-cancer agents and radiation therapy would be a highly effective treatment with few side-effects. Moreover, because TP53R2H may act as a homodimer (as R2 does), it might be possible to confer a dominant negative effect and suppress the activity of the enzyme by introducing mutated TP53R2H genes or TP53R2H protein into cancer cells, so both mutated TP53R2H genes and TP53R2H protein should be useful as therapeutic agents for highly malignant cancers with resistance to anti-cancer agents and radiation therapy. In addition, investigation of mutations to this gene should be useful in cancer diagnosis and prevention.